Schizophrenia and other mental illnesses
Chronic mental illnesses (CMI) like schizophrenia or the recurrent affective disorders are among the most debilitating (prevalence 1-10%) and costly diseases in the Western world. Tragically, the early onset of CMI in adolescence leads to in most cases to lifelong impairments and occupational disability. Yet, even though CMI have dramatic negative impact on individual patients, their relatives, and society, our biological understanding and options for novel strategies of efficient treatment to cure CMI are stalling.
The last decade has brought breakthroughs in the genetics of CMI, like the discovery of the disrupted-in-schizophrenia 1 (DISC1) gene, and many others. The identification of these candidate genes now allows analysis of the INter- and intracellular Signalling INSchizophrenia (hence the project acronym IN-SENS). In particular, the extended DISC1 pathway emerges as a converging point of signaling events relevant for CMI. Therefore, the detailed interdisciplinary analysis of this pathway could be a molecular Rosetta stone in deciphering the molecular foundations of behavior. Backed by this momentum, it is of importance to gain new perspectives on CMI and to fund this interdisciplinary Marie Curie Initial Training Network focussing on the molecular and cellular basis of CMI.
Despite their high prevalence (1-10% lifetime), research into the neurobiology of chronic mental illnesses (CMI) schizophrenia is still in its early days. Anachronistically, the diagnosis of “schizophrenia” is still purely clinical through interviewing of the self-reporting patient in the absence of “objective” tests, like blood sampling brain imaging or other. It is generally acknowledged that schizophrenia is likely to consist of a variety of diseases with different biological origins, but similar phenotypical or clinical symptoms. So-called positive and negative symptoms are hallmarks guiding the clinician to diagnosis. Positive symptoms are, for example, acute episodes of delusions, hallucinations, thought disorder and others, while negative and cognitive symptoms consist of a permanent and irreversible decline – but not loss – of intellectual and social functions disabling the patient to maintain their intellectual performance levels. Investigations into the neurobiology of SCZ over the course of the last century can, with gross simplification, be summarized as follows:
- The search for a neuropathology in post mortem brains of clinically diagnosed schizophrenic patients has not yielded a specific signature except the slight enlargement of the third ventricles. Even though claims have been made to signs of subtle disturbance of cortical architecture, these studies lack unequivocal replication (1). Inconsistencies in investigations on disturbed cortical architecture in schizophrenic patients may be explained by schizophrenia’s biological heterogeneity when using broad inclusion criteria, paired with low case numbers.
- The serendipitous discovery of the neuroleptics (2) and the subsequent revelation of their mechanism of action (3) has established dopamine as a central player in psychosis (that is, the acute, positive symptoms of SCZ). Over the years, a wealth of evidence has reinforced this hypothesis and the current opinion in the field is that the psychotic aspects of schizophrenia are due to a presynaptic, hyperdopaminergic state in the striatum, contrasting with a hypodopaminergic state in the prefrontal cortex (4, 5).
- A neurodevelopmental component in schizophrenia (6, 7) is subtle and can remain unnoticed in early childhood, becoming apparent only at adolescence or in conjunction with an exogenous or endogenous stressors (8).
- A genetic basis for schizophrenia has long been recognised, initially supported by sibling and twin studies, with monozygotic twins showing 50% or higher concordance for schizophrenia compared to 1% population average incidence (9, 10). Recent genetic linkage and their subsequent confirmation through association studies in various ethnic populations has led to the identification of candidate genes such as DISC1 (11), NRG1 (12), DTNBP1 (13) and others (14). Remarkably, these genetic studies led to the insight that diagnoses of ill individuals carrying the genetic markers crossed clinical diagnostic boundaries (15), i.e. gene carriers could show clinical phenotypes of schizophrenia or depression, suggesting that the biological fundamentals of CMI and the clinical phenotyping may not be well aligned. The study of these candidate genes has fundamentally changed molecular psychiatry since it is now possible to model behavioural, neuropathological and biochemical phenotypes in vivo by reverse genetic engineering of mutant candidate genes in animals (16, 17).
- DISC1: a molecular “Rosetta stone” of CMI. DISC1 is the product of a gene that is truncated in members of a Scottish large family as a consequence of a balanced translocation (ref. (11); discovered by partner 6). Carriers of the truncated DISC1 gene have an extraordinarily high prevalence of schizophrenia and other forms of CMI. This establishes DISC1 as a first gene product with a direct, causal role in the development of CMI. The key role of DISC1 for behavioral control has been corroborated by other linkage (18) and association studies in humans (19), and in genetic studies in animals (20). It has therefore been argued that DISC1 might be used as a “molecular Rosetta stone” to unveil the molecular mechanisms leading to CMI, just as mutations in the rare genes encoding amyloid precursor protein (APP) or the presenilins have been successfully used to resolve the molecular mechanisms of Alzheimer’ s disease (AD) (21). In this respect, it is conceivable that DISC1 partners or routes downstream of DISC1 itself, termed the “DISC1 pathway” (22) might be the relevant in CMI cases (22). There is also evidence showing that DISC1 protein pathology plays a key role in a subset of such “sporadic” CMI cases (23-25). Thus, the study of the structure, functions, partners and routes of the DISC1 pathway will provide essential keys on the molecular mechanisms underlying CMI.
Ever since the conceptualization of schizophrenia about a hundred years ago, there have been attempts to identify biological markers or correlates for all clinically defined schizophrenia cases, however without success. One reason is the apparent underlying biological heterogeneity of schizophrenia (26) that, as a clinically defined syndrome, could well comprise several different biological diseases, athough with simiar phenotype. Within IN-SENS, therefore, we are going to focus on one biological pathway that has convincingly and repeatedly (in different clinical contexts and animal models) been demonstrated to be involved in behavioural control, the extended disrupted-in-schizophrenia 1 (DISC1)-pathway. The idea of investigating a subgroup of schizophrenia defined by aberrant signalling in the DISC1 pathway is not to limit the informative value of IN-SENS’ research. Rather, by focussing on the study of DISC1 pathway, the IN-SENS consortium will be able to uncover key mechanisms of behavioural control and their interactions with environmental stressors. For example, it was also demonstrated that DISC1 modulates host responses to perinatal stress (27), a major risk factor for CMI, or by influencing the reaction to drugs like amphetamine, drugs where the intake has been shown to increase the later development of schizophrenia (28-30). Preceding the focus of IN-SENS on DISC1, the investigation of a rare gene (APP) has provided key scientific progress in elucidating Alzheimer’s disease the study of the rare gene APP in AD has been key for the incredible progress in revealing the molecular mechanisms (21).
IN-SENS scenario for a rapprochement of current clinical diagnosis and a future biological diagnosis of schizophrenia is depicted in Figure 1:
Figure 1. Scheme of the projected overlap between current clinical and future biological diagnoses of CMI. There will be overlap in assignment of clinical and biological diagnoses but no complete correspondence; however, the biological diagnoses will point to a similar biological mechanism which, in turn, will define common causal future pharmacotherapies.
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